Method for producing dihydroxyprogesterone derivatives



United States Patent ()fitlce 3,073,817 Patented Jan. 15, 1963 Thisinvention relates to tan improved process for the production ofcompounds of the formula and to novel intermediates produced in theprocess.

X in the above formula represents the halogens chlorine and bromine. Prepresents hydrogen and hydrocarbon and heterocyclic groups which aredefined hereinafter. Q represents hydrocarbon or heterocyclic groupslike those represented by P. P and Q may also join with the carbon towhich they are attached to form a cyclic group also defined below. I

In previous efforts to synthesize compounds of Formula I, one or moresteps in the processes have encountered difiiculties. These ditficultieshave been in the nature of either poor yields or inability to carrythrough the particular sequence with all types of substituent groupsincluding the destruction or removal of substituent groups in themolecule. The process of this invention employs a particular sequence ofsteps which are readily carried out, give high yields and may be appliedto materials having a wide variety of substituent groups without loss ordestruction of those groups during the processing.

According to this invention 1611,170L-dlllYdlXYPlO- gesterone is used asa starting material. This compound is reacted with a lower alkyl orthoester of formic acid to give the lower alkyl enol ether, lower alkylortho ester of the formula lower alkyl-O- chlorosuccinimide orN-bromosuccinimide in a mildly acidic butter such as acetic acid-sodiumacetate to ob tain the 6,8-chloro or 6B-bromo compound of the formula(m) CH8 Reaction of the compound of Formula 111- with a very dilutesolution of a Lewis acid such as hydrochloric acid, perchloric acid orthe like converts the former to the 618- chloro orofl-bromod6a,17ot-dihydroxyprogesterone of the formula (Iv) CH2 Thecompound of Formula IV may then be reacted with the aldehydes or ketonesdescribed below to yield compounds of Formula I. The acetalization orketalization is preferably carried out by treating a suspension orsolution of the dihydroxy compound of Formula IV in the aldehyde orketone (or in an organic solvent for the aldehyde or ketone if thelatter are solid) with an acid catalyst such as perchloric acid,p-toluenesulfonic acid, hydrochloric acid, etc., neutralizing the acid,and recovering the acetal or ketal compound of Formula I.

The products of Formula I are physiologically active substances whichpossess progestational activity when administered either orally orparenterally and therefore are useful in the treatment of suchconditions. as habitual or threatened abortion. They may be administeredin dosage forms such as tablets, capsules, elixirs, injectables and thelike according to conventional practice.

By following the particular sequence of process steps outlined above16a,17a-dihydroxyprogesterone may be. readily converted in a high yieldto the chlorinated or brominated products of Formula I. The.intermediate products may be isolated or the reaction mixture containing the intermediate may be immediately used in the subsequent step inthe synthesis.

The symbol 1 in Formula I above represents hydrogen or the moiety of anacetal or ketal, e.g. lower alkyl, halo lower alkyl, monocyclic aryl,monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclicheterocyclic lower alkyl. Q represents the same acetal or ketalmoieties. In addition P and Q may join with the carbon to which they areattached to form a monocyclic cycloalkyl or monocyclic heterocyclicradical.

Suitable aldehyde and ketone reactants which may be reacted with thedihydroxy compounds of Formula IV to obtain the products of Formula Iinclude lower alkanals of at least two carbon atoms, such asparalclehyde, propanal and hexanal; di(lowcr alkyl)ketones, such asacetone, diethylketone, dibutylketone, methylethylketone, andmethylisobutylketone; cycloalkanones, such as cyclobutanone,cyclopentanone, cyclohexanone, suberone, and cyclohexanone; cycloalkyl(lower alkanals), such as cyclopropylcarboxyaldehyde,cyclobutylcarboxaldehyde, cyclopentylcarboxaldehyde,cyclohexylcarboxaldehyde, cycloheptylcarboxaldehyde,cyclooctylcarboxaldehyde, cyclopropylacetaldehyde,cyclobutylacetaldehyde, cyclopentylacetaldehyde, cyclohexylacetaldehyde,fi-cyclopentylpropionaldehyde, 'y-cyclohexylbutyraldehyde, and 3-cyclopropylcaproaldehype; cycloalkyl (lower alkanones), such ascyclopropyl methyl ketone, cyclobutyl ethyl ketone, cyclopentyl propylketone, cyclopentylmethyl methyl ketone, cyclohexylmethyl ethyl ketone,cyclopentylethyl ethyl ketone, cyclopropylpropyl methyl ketone,cyclohexyl n-pentyl ketone,-,cyclohexyl methyl ketone, and cyclooctylmethyl ketone; dicycloalkyl ketones, such as dicyclopropyl ketone,dicyclobutyl ketone, dicyclopentyl ketone, dicyclohexyl ketone,cyclopentyl cyclohexyl ketone, cyclopropylmethyl cyclopropyl ketone,2-cyclobutyl ethyl cyclopropyl ketone, 3-cyclopentylmethyl cyclopentylketone, S-cyclohexylhexyl cyclohexyl ketone, di(cyclopentylmethyDketone,cyclohexylmethyl cyclopentyl ketone and di(4-cyclohexylpentyl)ketone;cycloalkyl monocyclic aromatic ketones, such as cyclopropyl phenylketone, cyclohexyl p-chlorophenyl ketone, cyclopentyl omethoxyphenylketone, cyclopentyl, o,p-dihydroxyphenyl ketone, cyclohexyl m-tolylketone, cyclopropyl p-ethylphenyl ketone, cyclopropyl p-nitrophenylketone, and cyclohexyl p-acetamidophenyl ketone; cycloalkyl(loweralkyl)monocyclic aromatic ketones, such as cyclopentylmethyl phenylketone; cycloalkyl monocyclic aromatic (lower alkyl) ketones, such ascyclopentyl benzyl ketone, cyclohexyl phenethyl ketone, and cyclobutylbenzyl ketone; cycloalkyl (lower alkyl)monocyclic aromatic (lower alkyl)ketones, such as cyclopentylmethyl benzyl ketones; cycloalkyl monocyclicheterocyclic ketones, such as cyclopentyl Z-furyl ketone, cyclohexylZ-thienyl ketone, and cyclopropyl 2-pyridinyl ketone; cycloalkyl (loweralkyl)monocyclic heterocyclic ketones, such as cyclopentylmethylZ-piperidinyl ketone, cyclohexylethyl 2-morpholinyl ketone andcyclopropyl 2-thienyl ketone; cycloalkyl monocyclic heterocyclic (loweralkyl) ketones, such as cyclopentyl-Z-thienyl ketone, cyclohexylfurfuryl ketone and cyclopropyl 2-piperidinylmethyl ketone; haloloweralkanals, such as chloral hydrate, trifluoroacetaldehyde hemiacetal, andheptafluorobutanal ethyl hemiacetal; halo-lower alkanones, such asl,1,l-trifiuroacetone; monocyclic carbocyclic aromatic aldehydes, suchas benzaldehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde andp-fluorobenzaldehyde), lower alkoxybenzaldehydes (e.g. o-anisaldehyde),di(lowcr alkoxy)benzaldehydes (e.g. veratraldehyde),hydroxybenzaldehydes (e.g. salicylaldehyde), dihydroxybenzaldehydes(e.g. resorcylaldehyde), lower alkyl benzaldehydes (e.g. m-tolualdehydeand p-ethylbenzaldehyde), di(lower alkyl)benzaldehydes (e.g.o,p-dimethylbenzaldehyde), nitrobenzaldehydes, acylamidobenzaldehydes(e.g. N-acetylanthranilaldehyde), and cyanobenzaldehydes; monocycliccarboxylic aromatic lower alkanals, such as phenylacetaldehyde,a-phenylpropionaldehyde, fl-phenylpropionaldehyde, 'y-phenyl-'butyraldehyde, and aromatically-substituted halo lower alkoxy, hydroxy,lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclicheterocyclic aldehydes, such as picolinaldehydes, furfural, thiophenecarbonals, and halo, lower alkoxy, hydroxy, lower alkyl, nitro, andcyano derivatives thereof; monocyclic heterocyclic lower alkanals,monocyclic carbocyclic aromatic ketones, such as acetophenone,a,m,a-trifluoroacetophenone, propiophenone, butyrophenone,valerophenone, isocaprophenone,

halophenyl lower alkyl ketones (e.g. p-chloroacetophenone andp-chloropropiophenone), (lower alkoxy) phenyl lower alkyl ketones (e.g.p-anisyl methyl ketone), di(lower alkoxy)phenyl lower alkyl ketones,hydroxyphenyl lower alkyl ketones, dihydroxyphenyl lower alkyl ketones(e.g. resacetophenone), (lower alkyl)phenyl lower alkyl ketones (e.g.methyl p-tolyl ketone), di(lowcr alkyl)-phenyl lower alkyl ketones(o,p-xyly1 methyl ketone), nitrophenyl lower alkyl ketones (e.g.p-nitroacetophenone), acylamidophenyl lower alkyl ketones, (e.g. acetylanilines), and cyanophenyl lower alkyl ketones; benzophenone, and monoor his substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro,acylamido and cyano derivatives thereof; monocyclic carbocyclic aromaticlower alkanones, such as l-phenyl-S-butanone and lphenyl-4-pentanone,and aromatically substituted derivatives thereof; monocyclicheterocyclic ketones, such as 2- acetylfuran, 2 benzoylfuran, 2acetylthiophene and alloxan; and monocyclic heterocyclic loweralkanones.

The following examples are illustrative of the process of thisinvention. All temperatures are expressed in degrees centigrade.

EXAMPLE 1 3-Eth0xy-1 6a,17a-Ethoxymethylenedioxy-A Pregnadiene-ZO-One Toa suspension of 5.0 g. of 16u,17a-dihydroxyprogesterone in a mixture of38 ml. of dioxane, 0.5 ml. of absolute ethanol and 5.0 ml. of ethylorthoforrnate 3.5 ml. of a dioxane solution containing 0.18 ml. ofsulfuric acid are added. Within a minute the steroid dissolvescompletely and after another minute the product begins to separate fromsolution as crystals. The suspension is stirred for 20 minutes, then 2.0ml. of pyridine are added and the mixture diluted with 30 ml. of water.The crystals are filtered, washed with methanol-water 1:1) and dried togive 5.0 g. of 3-ethoxy-16a,17a-ethoxymethylenedioxy-A-pregnadiene-20-one having a melting point 223-225 [od 63 (chlf.);Afiffi" 5.83, 6.05, 6.14 1; M33 Analysis.'Calcd. for C H O (430.56): C,72.52; H,

8.90; 2OC H 20.94. Found: C, 72.53; H, 8.59; OC H 19.95.

To a stirred suspension of 300 mg. (0.697 mmol) of 3- ethoxy 1611,1711ethoxymethylenedioxy A pregnadiene-ZO-one in 10 ml. of dioxane asolution of 94 mg. (0.75 mmol) of N-chlorosuccinimide in 2 ml. ofdioxane are added followed by 4.0 ml. of a buffer containing 6.6 g. ofsodium acetate and 6.6 ml. of acetic acid per ml. of solution. Themixture is stirred at room temperature for 45 minutes during which timethe steroid dissolves. Addition of water to the solution gives crystalswhich are filtered, washed with water and dried. Recrystallization fromacetone-hexane gives mg. of 6,8- chloro-l 6oz,17a-ethoxymethylenedioxyprogesterone having a melting point l9l193;

Slow dilution with water gives a crystalline precipitate which isfiltered, washed with water and dried. Re-

S crystallization from acetone-hexane gives 55 mg. of 6 8-chloro-l6a,17a-dihydroxyprogesterone having M.P. 210- 212;

[111 +11; M11 237 mu (e=15,200); Ami? 2.90, 5.88,

EXAMPLE 4 6p-Chl0r0-1 6 oz, 1 7 oz-D ih ydroxy progesterone 160:,17u-Acetonide A solution of 25 mg. of6fl-chloro-16a,17a-dihydroxyprogesterone in 1.5 ml. of acetonecontaining 0.001 ml. of perchloric acid (70%) is left at roomtemperature for 2 hours. After neutralization with dilute sodiumbicarbonate the solution is diluted with water and the precipitatefiltered, washed with water and dried to give 27 mg. of6,8-chloro-16a,l7a-dihydroxyprogesterone 16oc,17oL-8.C6l20- nide.

EXAMPLE 5 By substituting N-bromosuccinimide for the N-chlorosuccinimidein the procedure of Example 2 and continuing according to the procedureof Examples 3 and 4, there are obtained6fl-bromo-l6a,l7a-ethoxymethylenedioxyprogesterone,6/3-bromo-16a,l7a-dihydroxyprogesterone and6/3-bromo-16a,l7a-dihydroxypr0gesterone 16,17-acetonide, respectively.

EXAMPLE 6 By substituting acetophenone for the acetone in Example 4,there is obtained the 16a,l7u-acetophenone derivative of6,8-chloro-16a,l7a-dihydroxyprogesterone.

EXAMPLE 7 By substituting monofluoroacetone for the acetone in Example4, there is obtained the 16a,l7a-monofluoroacetone derivative of6fi-chloro-16u,l7a-dihydroxyprogesterone.

By similarly using either N-chlorosuccinimide or N- bromosuccinimideaccording to the procedure of Examples 2 or 5 and substituting any ofthe other aldehydes or ketones referred to (see column 3, line 1, tocolumn 4, line 19) above for the acetone in the procedure of Example 4the corresponding 65-chloroor 6/3-bromo-16u, 17u-dihydroxyprogesteronederivatives are obtained.

What is claimed is:

1. A process for the production of compounds of the formula wherein X isa member of the group consisting of chlorine and bromine and P is amember of the group consisting of hydrogen, lower alkyl, halo loweralkyl, monocyclic lower alkyl, monocyclic cycloalkyl lower alkyl,monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclicand monocyclic heterocyclic lower alkyl, and Q is a member of the groupconsisting of lower alkyl, halo lower alkyl, monocyclic cycloalkyl,monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryllower alkyl, monocyclic heterocyclic and monocyclic heterocyclic loweralkyl,- and together with the carbon to which they are joined P and Qare selected from the group consisting of monocyclic cycloalkyl andmonocyclic heterocyclic,

which comprises reacting 16m,l7u-dihydroxyprogesterone with a loweralkyl ortho ester of formic acid to produce the lower alkyl enol ether,lower alkyl, ortho ester of said 16a,17a-dihydroxyprogesterone, reactingthe latter with a member of the group consisting of N-chlorosuccinimideand N-bromosuccinimide in a buffer, treating the reaction product with adilute acid solution and reacting the dihydroxyprogesterone product witha compound of the formula wherein P and Q are as above defined.

2. A process which comprises reacting l6a,l7a-dihydroxyprogesterone withethyl orthoformate to obtain 3- ethoxy 16a,l7a ethoxymethylenedioxy Apregnadiene-ZO-one, reacting the last named compound with N-chlorosuccinimide to obtain6fl-chloro-16a,17a-ethoxymethylenedioxyprogesterone, treating the lastnamed compound with dilute mineral acid to obtain 6fi-chloro-16a,l7a-dihydroxyprogesterone and ketalizing the last named product withacetone to obtain 6B-chlorol6u,l7udihydroxyprogesterone 16,17-acetonide.

3. A process which comprises reacting 16u,17u-dihydroxyprogesterone withethyl orthoformate to obtain 3- ethoxy 16ot,17oc ethoxymethylenedioxy Apregnadiene-ZO-one, reacting the last named compound with N-bromosuccinimide to obtain 6fi-b10mO-16oc,170c-ethOXY-methylenedioxyprogesterone, treating the last named compound with dilutemineral acid to obtain 6,8-bromo-l6a, 17a-dihydroxyprogesterone andketalizing the last named product with acetone to obtain6]3-b10mO-16oc,17a-dihydroxyprogesterone 16,17-acetonide.

4. A compound of the formula I --0 H x O O-lower alkyl lower alkyl- 0 5.3 ethoxy l6a,l7u ethoxymethylenedioxy A pregnadiene 20-one.

6. A compound of the formula wherein X is a member of the groupconsisting of chlorine and bromine.

7. 618 chloro :,170; ethoxymethylenedioxyprogesterone.

8. 6,8 bromo l6o,17ot ethoxymethylenedioxyprogesterone.

9. 6 3-chloro-l6a,17u-dihydroxyprogesterone.

10. 6,8-bromo-16a,17a-dihydroxyprogesterone.

No references cited.

1. A PROCESS FOR THE PRODUCTION OF COMPOUNDS OF THE FORMULA